In:
Genes & Development, Cold Spring Harbor Laboratory, Vol. 25, No. 16 ( 2011-08-15), p. 1734-1745
Abstract:
The miR-17∼92 cluster is a potent microRNA-encoding oncogene. Here, we show that miR-17∼92 synergizes with loss of Rb family members to promote retinoblastoma. We observed miR-17∼92 genomic amplifications in murine retinoblastoma and high expression of miR-17∼92 in human retinoblastoma. While miR-17∼92 was dispensable for mouse retinal development, miR-17∼92 overexpression, together with deletion of Rb and p107 , led to rapid emergence of retinoblastoma with frequent metastasis to the brain. miR-17∼92 oncogenic function in retinoblastoma was not mediated by a miR-19 /PTEN axis toward apoptosis suppression, as found in lymphoma/leukemia models. Instead, miR-17∼92 increased the proliferative capacity of Rb / p107 -deficient retinal cells. We found that deletion of Rb family members led to compensatory up-regulation of the cyclin-dependent kinase inhibitor p21Cip1. miR-17∼92 overexpression counteracted p21Cip1 up-regulation, promoted proliferation, and drove retinoblastoma formation. These results demonstrate that the oncogenic determinants of miR-17∼92 are context-specific and provide new insights into miR-17∼92 function as an RB -collaborating gene in cancer.
Type of Medium:
Online Resource
ISSN:
0890-9369
,
1549-5477
DOI:
10.1101/gad.17027411
Language:
English
Publisher:
Cold Spring Harbor Laboratory
Publication Date:
2011
detail.hit.zdb_id:
1467414-2
SSG:
12
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